Diagnosis and

Tre a t m e n t o f M a j o r
D e p re s s i v e D i s o rd e r
Laili Soleimani, MD, MSca, Kyle A.B. Lapidus, MD, PhD
a
,
Dan V. Iosifescu, MD, MScb,c,d,*

KEYWORDS
 Major depressive disorder  Comorbid medical illness
 Comorbid neurologic illness  Antidepressant treatments
 Pharmacotherapies  Psychotherapies  Somatic treatments

Major depressive disorder (MDD) encompasses a large number of psychobiological

syndromes with the core features of depressed mood and/or loss of interest associ-
ated with cognitive and somatic disturbances, which causes significant functional
impairment. Depressive disorders are classified as mood disorders and are distin-
guished from bipolar disorders by the absence of manic episodes. According to the
American Psychiatric Association (APA) Diagnostic and Statistical Manual of Mental
Disorders, fourth edition, Text Revision (DSM-IV-TR), depressive disorders include
MDD (Box 1), dysthymic disorder (low-grade chronic depression occurring more
than 50% of the days for at least 2 years), and minor depression (minimum of 2
depressive symptoms present for at least 2 weeks).1
Large epidemiologic studies suggest that major depressive disorder is common,2,3
with a lifetime prevalence of 16.6%, occurring with approximately twofold higher
frequency in women compared with men.2,3 MDD aggregates in families; it is 1.5 to
3 times more common in individuals with first-degree biologic relatives affected with
MDD compared with the general population.4 The point prevalence of MDD has
been reported to be 10% in the primary care setting, 15% to 20% in the nursing
home population, and 22% to 33% in medically ill patients.5–7
Historically, MDD pathology has been associated with brain monoamine neuro-
transmitter or receptor abnormalities. Studies of cerebrospinal fluid chemistry,

L. Soleimani and K.A.B Lapidus contributed equally (ie, shared first authorship).
a
Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place
Box 1230, New York, NY 10029, USA
b
Mood and Anxiety Disorders Program, Mount Sinai School of Medicine, One Gustave L. Levy
Place Box 1230, New York, NY 10029, USA
c
Psychiatry Department, Massachusetts General Hospital, Boston, MA, USA
d
Harvard Medical School, Boston, MA, USA
* Corresponding author. Mood and Anxiety Disorders Program, Mount Sinai School of
Medicine, One Gustave L. Levy Place Box 1230, New York, NY 10029.
E-mail address: [email protected]

Neurol Clin 29 (2011) 177–193

doi:10.1016/j.ncl.2010.10.010 neurologic.theclinics.com
0733-8619/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
178 Soleimani et al

Box 1
Criteria for major depressive episode (DSM-IV-TR)1

 At least 5 of the following symptoms must be present continuously for 2 weeks; at least 1
should be either depressed mood or lack of interest:
 depressed mood (or irritability in children and adolescents)
 lack of interest or pleasure
 appetite change or weight change
 insomnia or hypersomnia
 psychomotor agitation or retardation
 fatigue or loss of energy
 feelings of worthlessness or guilt
 decreased concentration
 recurrent thoughts of death and suicidal ideation
 No history of bipolar disorder (eg, manic or hypomanic episodes)
 Symptoms should cause clinically significant functional impairment
 Symptoms should not be secondary to a substance (eg, a drug of abuse, a medication) or
a general medical condition (eg, hypothyroidism)
 Symptoms are not better accounted for by bereavement
From American Psychiatric Association. Diagnostic and statistical manual of mental disorders
(DSMIV-TR). Fourth edition. Washington, DC: American Psychiatric Association; 2000. p. 356;
with permission.

neuroreceptor, and transporter systems, as well as clinical response to monoamin-

ergic agents, have suggested that serotonergic, noradrenergic, other neurotrans-
mitter, and neuropeptide systems may be abnormal in MDD (reviewed in Refs.8,9).
However, there has been an increasing focus on the interplay of environmental factors
with genetic and neuroendocrine systems and the involvement of intracellular
signaling pathways. The hypothalamic-pituitary-adrenal axis has been suggested to
mediate environmental stress and contribute to neuronal atrophy. The common
cellular abnormality in various forms of depression may be reduced cellular resilience
caused by decreased expression of several neurotrophic factors (eg, brain-derived
neurotrophic factor, Bcl-2).8–11

EVALUATION
Diagnostic Evaluation
Clinical suspicion is key to the diagnosis of MDD. Patients should be asked about
depressed mood and/or lack of interest or pleasure when they present with nonspe-
cific symptoms suggestive of depression (Box 2). Clinicians should evaluate the
patient for the following features: onset, duration, accompanying psychological symp-
toms, possible psychosocial precipitating factors (eg, relationship problems, work-
related stressors, or living conditions), and the effect of these symptoms on the
patient’s daily life and function. A key component of the evaluation is determining
the absence or presence of suicidal ideations and/or homicidal ideations, in which
case the clinician should also inquire whether the patient has intent to hurt self or
others and whether a plan has been made.
 Major Depression: Diagnosis and Treatment 179

Box 2
Common symptoms of depression

Depressed mood
Anxiety, excessive worrying
Irritable mood
Anger attacks
Crying spells
Loss of interest or pleasure
Distractability
Change in appetite
Change in sleep
Fatigue
Pain (eg, headaches, back pain)
Muscle tension
Heart palpitations
Guilt
Feelings of worthlessness
Recurrent thoughts of death or suicide

Detailed history of past depressive or manic episodes, other psychiatric disorders,

and possible use of alcohol or other substances should be obtained because these
can significantly influence diagnosis and treatment decisions.
Some depressive disorders may be secondary to medical conditions or medications
(Box 3); the diagnosis will rest on physical signs and symptoms, medical history, and
medication history.
Laboratory testing, including thyroid function tests, B12, and folate levels, may aid in
reaching an accurate diagnosis and uncovering medical problems partially or fully
responsible for the psychiatric presentation.

Box 3
Examples of medical conditions causing depressive symptoms

Autoimmune disorders (eg, systemic lupus erythematosus, rheumatoid arthritis)

Neurologic disorders (eg, stroke, dementias, multiple sclerosis, seizure disorder, Huntington
disease, traumatic brain injury)
Endocrine disorders (eg, hypercalcemia, hypercortisolism, hyperparathyroidism,
hyperthyroidism, hypoparathyroidism, hypothyroidism)
Malignancies (eg, gastrointestinal cancer, pancreatic cancer)
Infectious disease (eg, hepatitis, human immunodeficiency virus, mononucleosis)
Medications or substances: antihypertensive medications (eg, propranolol, thiazides,
clonidine), anticholinergic agents, anticonvulsant agents, oral contraceptives, sedatives (eg,
barbiturates, benzodiazepines), antiparkinsonian medications (eg, methyldopa, amantadine),
and alcohol
180 Soleimani et al

Measuring Depression Severity with Standardized Scales

Clinician-administered and self-rated scales allow a more objective assessment of
depression severity but need to be interpreted in the context of patients’ symptoms
and medical conditions. Such scales can also be useful in monitoring the effect of
treatments. Because multiple well-established and validated scales are available,
physicians can choose appropriate measures based on their patient populations
and practice settings (Box 4).
The Hamilton Rating Scale for Depression (HAM-D), the most widely used clinician-
administered instrument, focuses on biologic and somatic symptoms of MDD; the 17-
item version is the most frequently used subscale of the original 31-item HAM-D.13,14
The Montgomery-Asberg Depression Rating Scale (MADRS), has a lower number of
items, less overlap with anxiety symptoms, and is one of the most user-friendly
observer-rating scales.15
Self-administered instruments require less interaction with the clinician. The Quick
Inventory of Depressive Symptomatology (QIDS-SR; http://www.ids-qids.org) over-
laps well with the Diagnostic and statistical manual symptoms of MDD and has
been extensively validated.12 The Beck Depression Inventory (BDI), is an older self-
rating scale that preferentially detects and rates cognitive aspects of depression,
with an emphasis on self-esteem.16 The Geriatric Depression Scale (GDS) is a 30-
item self-administered scale that includes questions about symptoms such as cogni-
tive complaints, self-image, and loss; these symptoms are believed to be particularly
relevant in late-life depression.17,18

Safety Evaluation
Suicide is one of the most severe and potentially fatal mental health–related emergen-
cies and is 20 times more common in patients suffering from MDD than in healthy pop-
ulations. Clinicians play an important role in the screening and prevention of suicide
because most suicidal patients have contact with their physicians within the month
before suicide.19 Therefore, physicians should always ask about and document
thoughts of death in patients with depression or other mental health problems
(Box 5). Positive responses should be followed by assessment of the content of the
thoughts (plans or intent), history of past attempts, triggering factors, and other asso-
ciated risk factors. The physician should also work with both patient and family to limit
access to lethal means (eg, firearms and large amounts of medications), and, when
necessary, consider psychiatric consultation and/or hospitalization.

Box 4
Examples of rating scales for depressive symptoms

Clinician administered
Hamilton Rating Scale for Depression (HAM-D)
Montgomery-Asberg Depression Rating Scale (MADRS)
Self-report scales
Beck Depression Inventory
Quick Inventory of Depressive Symptoms–Self-report (QIDS-SR;12 http://www.ids-qids.org)
Geriatric Depression Scale (GDS; http://www.stanford.edu/wyesavage/GDS.html)
 Major Depression: Diagnosis and Treatment 181

Box 5
Suicidal thought item from Montgomery-Asberg Depression Rating Scale15:

Clinician’s question
This last week have you had any thoughts that life is not worth living, or that you would be
better off dead? What about thoughts of hurting or even killing yourself? If YES: What have
you thought about? Have you actually made plans? (Have you told anyone about it?)
Responses (with anchor points for consistent rating of patient responses)
0: Enjoy life or take it as it comes
1
2: Weary of life. Only fleeting suicidal thoughts
3
4: Probably better off dead. Suicidal thoughts are common, and suicide is considered as
a possible solution, but without specific plans or intention
5
6: Explicit plans for suicide when there is an opportunity. Active preparation for suicide
From Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br
J Psychiatry 1979;134:398; with permission.

DIFFERENTIAL DIAGNOSIS

Depression is a common symptom among many psychiatric conditions. Table 1 lists

the most common psychiatric differential diagnoses of MDD.

SPECIAL MDD POPULATIONS

Depression in Patients with General Medical Conditions
Depression is more prevalent among patients with medical illness (including cardio-
vascular disease, diabetes, and other conditions listed in Box 3) and has been sug-
gested to increase mortality by as much as 4.3 times.20 Major depression itself is
harder to treat in medically ill patients.21 It is important to understand the relationship
between depressive symptoms and the underlying medical conditions. For example,
in patients with depression and chronic pain, controlling the pain often results in signif-
icant improvement of mood symptoms. Treating both medical and depressive symp-
toms can improve the outcome of medical treatment and adherence to medical
therapy and rehabilitation. Atypical depressive symptoms and associated positive
laboratory findings for a nonprimary depressive disorder warrant a full medical
work-up.

Depression in Patients with Stroke

About one-third of all patients with stroke develop poststroke depression (PSD).22
PSD can contribute to the disability caused by the stroke and can increase mortality.
A meta-analysis of 51 population-, hospital-, and rehabilitation-based stroke studies
conducted between 1977 and 2002 showed that depression was associated with
physical disability, stroke severity, and cognitive impairment.22 A prospective,
randomized controlled trial of 448 patients with stroke evaluated for depression 1
month after stroke and followed up at 12 and 24 months showed that mood symptoms
were associated with increased 12- and 24-month mortality after adjustment for other
182 Soleimani et al

Table 1
Psychiatric differential diagnoses of major depression

Differential Diagnoses Characteristic Feature

Nonpathologic periods Short duration, few associated symptoms, and lack of
of sadness significant functional impairment or distress
Bereavement In response to the loss of a loved one, usually
ameliorating within 2 months and not lasting more
than 6 months
Adjustment disorder with In response to an immediate stressor; does not meet full
depressed mood criteria for a major depressive episode
Seasonal depression Recurrent episodes with clear seasonal pattern (onset in
fall or winter and full remission usually by the spring)
Premenstrual dysphoric Characterized by significant depressed mood, anxiety,
disorder and irritability during the 1–2 weeks before menses
and resolving with menses
Postpartum depressive Full depressive episode with an onset within a few
disorder months after delivery. To be differentiated from
postpartum blues (fewer symptoms, onset shortly
after delivery, and subsides usually within 3 weeks)
Bipolar I or bipolar II disorder History of 1 or more manic, mixed, or hypomanic
episodes
Mood disorder caused by Direct physiologic effect of a general medical condition
a general medical condition
Substance-induced mood Caused by the direct physiologic effect of a substance
disorder (including medication); symptoms develop within
a month of substance use
Dysthymic disorder Depressed mood present more than 50% of days in a
2-year period, in the absence of major depressive
episodes
Schizoaffective disorder Recurrent periods of at least 2 weeks of delusions or
hallucinations; at least some of these periods occur in
the absence of prominent mood symptoms
Schizophrenia, delusional Depressive symptoms are brief relative to the total
disorder, psychotic disorder duration of the psychotic disturbance (eg, delusions,
not otherwise specified hallucinations)
Posttraumatic stress disorder Occurs within the 6 months following a stressful event;
characterized by hyperarousal, episodes of
flashbacks, nightmares, detachment, numbness,
maladaptive coping responses, and excessive use of
alcohol and drugs
Dementia Characterized by a progressive history of declining
cognitive functioning (usually before depressive
symptoms). Low scores (usually <23) on the mini–
mental status examination

identified risk factors.23 The incidence of PSD peaks 3 to 6 months after the stroke;
risk factors include severity of disability, poor social support, personal and family
history of depression, and the development of aphasia. Numerous studies have
reported increased risk of PSD in left anterior hemisphere strokes or basal ganglia
(reviewed in Refs.24,25).
Although multiple studies support the use of selective serotonin reuptake inhibitors
(SSRIs) and tri/tetracyclic antidepressants (TCAs) in PSD, there are no well-designed
 Major Depression: Diagnosis and Treatment 183

studies that guide therapeutic decision making for patients with PSD.26,27 More than
60% of patients with PSD respond to antidepressants, with no particular class of anti-
depressant showing a clear advantage in treatment efficacy. The data are less conclu-
sive regarding psychostimulants because of a lack of randomized controlled trials.
Overall, antidepressants and stimulants are well tolerated in patients with stroke
(reviewed in Ref.28). In a recent randomized controlled study both the SSRI escitalo-
pram and problem-solving therapy (a form of cognitive-behavioral therapy [CBT])
were more effective than placebo in preventing development of PSD in 176 at-risk
patients.29

Depression in Patients with Multiple Sclerosis

Cross-sectional studies estimate that almost half of patients with multiple sclerosis
(MS) develop depression during the course of their disease.30 Based on a large-scale
Canadian national survey, the 12-month prevalence of MDD is 15% in this population
of patients with MS.31–33 Multiple studies have shown a lower quality of life, increased
risk of suicidal ideation, and impaired cognitive function in patients with MS with
depression (reviewed in Ref.31).
The consensus from research suggests that the development of depression in
patients with MS is multifactorial: psychosocial stress related to the diagnosis and
exacerbation or progression of disability, as well as MS-related brain changes (eg,
neuroinflammatory and neurodegenerative changes) and underlying preexisting
psychiatric comorbidities, can predispose patients to depression (reviewed in
Ref.34). A recent multicenter, observational study of 798 patients suggested that
past history of depression (rather than specific MS treatments, ie, interferon or glatir-
amer acetate) predicted emergence of depressed mood.35
Screening and detection of depression in patients with MS is particularly important
because depression has also been identified as one of the 3 most significant factors
contributing to noncompliance with immune-modulatory treatment.36 A follow-up
study of 85 patients with MS who developed depression after initiation of interferon
therapy showed improved treatment adherence with both psychotherapy and antide-
pressants.37 The general consensus is that the combination therapy is the best
approach to treatment of depression in this population.38,39
SSRIs are often the first-line treatment option because of their safer side effect
profile, fewer contraindications, and significantly lower chance of negative drug inter-
actions. Based on tolerability rather than any evidence for differences in efficacy,
TCAs and monoamine oxidase inhibitors (MAOIs) are generally used in patients in
whom SSRIs have been ineffective. However, for patients experiencing chronic pain
or sleep disturbance, TCAs (eg, nortriptyline, amitriptyline) may be the treatment of
choice because of their ability to reduce pain and because of their sedative effects.40
Counseling and social support have also been found to be helpful in the treatment of
depression in these chronically ill patients.34,41

Depression in Patients with Parkinson Disease

Depression is the most common psychiatric disturbance in patients with Parkinson
disease (PD) and, although the prevalence varies across different studies, depression
is estimated to occur in approximately half of all patients with PD.42,43 Despite its high
prevalence, depression is frequently underdiagnosed and undertreated in these
patients. This is most likely because of the challenge of distinguishing PD symptoms,
such as psychomotor slowing and blunted affect, from depressive symptoms. Degen-
eration of monoaminergic neurotransmitter systems and frontocortical dysfunction
have been suggested as the underlying mechanism of depression in PD.44,45
184 Soleimani et al

Randomized controlled studies have shown that TCAs and bupropion are effica-
cious for the treatment of depression in Parkinson disease.46–48 SSRIs have shown
similar efficacy compared with TCAs, but show a different profile of adverse effects,
which may be particularly favorable in elderly patients.49 A recent double-blind,
randomized, placebo-controlled study showed that desipramine and citalopram
each improved depressive symptoms after 30 days, but that mild adverse events
were twice as frequent in the desipramine-treated group.50 A randomized multicenter
national study showed that pramipexole improved motor symptoms but also had anti-
depressant efficacy that was comparable with sertraline and specifically improved
anhedonia.49,51 Although based on this single study, pramipexole could be recom-
mended as a first-line treatment in patients with PD and depression. Lithium,
a commonly used augmentation agent with antidepressant drugs, should be avoided
in patients with PD because of the risk of tremor induction.49

TREATMENT OF MDD

Useful treatments for depression include pharmacotherapy, focused psychother-

apies, somatic treatments, and lifestyle changes.

Pharmacotherapy
Commonly used antidepressants and doses are listed in Table 2. Although several
pharmacologic agents are approved by the US Food and Drug Administration (FDA),
none are clearly superior in efficacy. They differ in pharmacologic and side effect
profile (Table 3). Although onset of antidepressant efficacy may vary for individual
patients, onset of efficacy may require 4 to 6 weeks of treatment with most currently
available agents, whereas full efficacy may require 8 to 12 weeks.52,53 As a general
rule, antidepressant side effects can be minimized by slowly increasing dosage (espe-
cially in the elderly), although this strategy may also delay the onset of efficacy.

SSRIs
SSRIs are frequently used as a first-line treatment of depressive disorders because
their specificity results in fewer drug-drug interactions, safety in overdose, and a favor-
able side effect profile.54 They also effectively treat anxiety disorders and other psychi-
atric comorbidities frequently associated with depression.55,56

Serotonin and norepinephrine reuptake inhibitors

Serotonin-norepinephrine reuptake inhibitors (SNRIs) are also effective in treating
depression and anxiety. They may be particularly useful in SSRI nonresponders and
in specific chronic pain conditions.57 However, they tend to be more expensive.

TCAs
TCAs are older, inexpensive agents that also act primarily by inhibiting serotonin and
norepinephrine reuptake, are effective as antidepressants, and effectively treat chronic
pain.58 They also interact with many other receptors, which may contribute to their effi-
cacy, but produces side effects that may limit tolerability and compliance.59 TCAs block
muscarinic acetylcholine receptors, leading to anticholinergic side effects (see
Table 3). The risk of confusion and disorientation is most significant in elderly patients,
and delirium has been reported in 5% of elderly patients taking TCAs.60 TCAs also
antagonize histamine H1 receptors and a1 adrenergic receptors; caution is advised in
patients with narrow angle glaucoma, prostatic hypertrophy, or low blood pressure.
Because TCAs prolong cardiac repolarization, they can act similarly to class I antiar-
rhythmic agents. Their toxic effects on cardiac conduction, which make TCAs
 Major Depression: Diagnosis and Treatment 185

Table 2
Recommended dosages for commonly prescribed antidepressants

Drug Usual Dose (mg/d) Initial Dose (mg/d) Notes

SSRIs
Citalopram (Celexa) 20–60 10–20 Few drug interactions
Escitalopram (Lexapro) 10–20 5–10 Few drug interactions
Paroxetine (Paxil and 10–50 10–20 Short half-life
Paxil CR)
Sertraline (Zoloft) 25–200 25–50
Fluvoxamine (Luvox) 50–300 25–50
Fluoxetine (Prozac) 10–60 10–20 Longest half-life
SNRIs
Venlafaxine (Effexor 75–225 37.5
and Effexor XR)
Desvenlafaxine (Pristiq) 50–100 50
Duloxetine (Cymbalta) 40–120 20–40
Tricyclic/Tetracyclic Antidepressants
Amitriptyline (Elavil) 100–300 10–50
Clomipramine 100–250 25
(Anafranil)
Doxepin (Adapin) 100–300 25–50
Imipramine (Tofranil) 100–300 10–25
Trimipramine 100–300 25–50
(Surmontil)
Desipramine 100–300 25–50 Favorable tolerability
(Norpramin)
Nortriptyline (Pamelor) 50–150 10–25 Favorable safety,
tolerability
Protriptyline (Vivactil) 15–60 10 Activating
Amoxapine (Asendin) 100–400 50
Maprotiline (Ludiomil) 100–225 50
MAOIs
Phenelzine (Nardil) 45–90 15
Tranylcypromine 30–60 10
(Parnate)
Isocarboxazid (Marplan) 30–60 20
Selegiline (Eldepryl) 30–40 10 Selective MAO-B
Inhibitor at low doses
Selegiline transdermal 6–12 6
(Emsam)
Other Antidepressants
Bupropion (Wellbutrin) 300–450 75–150 Available as SR and XL/
XR
Mirtazapine (Remeron) 15–45 15

Abbreviations: MAOI, monoamine oxidase inhibitor; SNRI, serotonin-norepinephrine reuptake

inhibitor; SSRI, selective serotonin reuptake inhibitor.
186 Soleimani et al

Table 3
Important side effects of antidepressants

Drug Class Important Side Effects

SSRIs and SNRIs Nausea, decreased appetite, weight loss, diaphoresis,
insomnia, sedation, nervousness, sexual dysfunction,
headache, dizziness
TCAs Anticholinergic: dry mouth, constipation, hyperthermia, sinus
tachycardia, blurred vision, urinary retention, cognitive/
memory impairment
Antihistaminic: sedation, increased appetite, weight gain,
hypotension
Antiadrenergic: postural hypotension, dizziness, tachycardia
Reduced seizure threshold, sexual dysfunction, cardiac
conduction effects similar to class 1A antiarrhythmics,
cardiotoxicity in overdose
MAOIs Insomnia, sedation, weight gain, orthostatic hypotension,
sexual dysfunction
Less common: pyridoxine deficiency with parasthesias, tremor,
anticholinergic effects
Hypertensive crisis: occurs with tyramine ingestion (eg, aged
cheese and meats, fava beans, soy sauce)
Serotonin syndrome: life threatening with rapid onset of
hyperthermia, hypertension, tachycardia, shock
Bupropion (Wellbutrin) Agitation, dry mouth, insomnia, nausea, constipation, tremor,
headache
Increased seizure risk
Mirtazapine (Remeron) Antihistaminic: sedation, increased appetite, weight gain,
hypotension, dry mouth, constipation, dizziness

potentially lethal in overdose, can be detected by QTC prolongation. Therefore, obtain-

ing an electrocardiogram is advisable before and 4 weeks after initiating TCA treat-
ment.61 Plasma levels can help guide dosage adjustments.62 In PD, a controlled trial
showed superiority of TCA treatment, with a response rate of 53%.63

MAOIs
MAOIs are most often used in patients with atypical depression or in treatment-resis-
tant patients who fail trials of other medications. In patients with atypical depression,
MAOI response rates of 59% to 71% have been reported.64,65 MAOIs can also be effec-
tive in PD, and may be particularly suited for treating depression in these patients. They
act by inhibiting monoamine oxidase (MAO)-A and -B, enzymes that break down mono-
amines including serotonin, dopamine, and norepinephrine. These MAO enzymes are
widely distributed throughout the body and can be found throughout the gastrointes-
tinal tract and liver, and in platelets, as well as in neurons and glia. Several MAOIs avail-
able in the United States (eg, phenelzine, tranylcypromine) irreversibly inhibit both
MAO-A and MAO-B, so their effects persist through several drug-free days until
enzyme stores are replenished. Intake of foods containing the sympathomimetic amine
tyramine can result in potentially lethal hypertensive crises. Serotonin syndrome is also
possible with MAOIs, TCAs, and SSRIs; it involves cognitive changes such as confusion
or agitation, autonomic dysregulation such as fever, changes in blood pressure, diar-
rhea, flushing, and diaphoresis, as well as hyperreflexia, myoclonus, and tremor.66
Tryptophan-containing foods also pose a risk for serotonin syndrome. To avoid sero-
tonin syndrome, a washout period of at least 2 weeks (5 weeks for fluoxetine, because
 Major Depression: Diagnosis and Treatment 187

of its longer half-life) is recommended when switching to or from an MAOI.67 Other

medications that may react with MAOIs to cause hypertensive crises or serotonin
syndrome include meperidine, tramadol, dextromethorphan, and SSRIs.

Other agents
Additional antidepressants include bupropion and mirtazapine. These agents are
generally safer in overdose than TCAs, and mirtazapine has a particularly favorable
safety profile, with a large study reporting no fatalities in 2599 suicidal ingestions.68
Bupropion has dopaminergic properties and energizing effects; it is used as an aid
for smoking cessation and has few sexual side effects. Because of increased seizure
risk, bupropion is contraindicated in patients with seizure disorders or bulimia. Mirta-
zapine can be easily combined with other agents because of limited drug-drug inter-
actions. Its side effects, such as weight gain and sedation, result mainly from
histamine H1 receptor blockade.69
Augmenting standard antidepressants with atypical antipsychotics is the best
shown augmentation strategy in treatment-resistant depression.70,71 Many high-
quality studies also support antidepressant augmentation with lithium72 or thyroid
hormones,73 although most of those studies were carried out with tricyclic antidepres-
sants, and few of those studies included modern antidepressants.74 Smaller studies
also support the role of certain natural remedies (eg, S-adenosyl-methionine),75 and
psychostimulants as augmentation strategies in cases of partial or nonresponse to
an antidepressant agent.

Psychotherapy
CBT (including mindfulness and relaxation techniques), behavioral therapy, and inter-
personal therapy are efficacious in treating MDD. Although short-term dynamic and
emotion-focused psychotherapies may also be efficacious, less evidence supports
these strategies for the treatment of depressed patients.76 Although remission rates
with cognitive therapy or medication alone have been reported to reach 40% to
46%, patients with moderate or severe depression may benefit more from a combina-
tion of pharmacotherapy and psychotherapy.77

Somatic Treatments
Electroconvulsive therapy (ECT) is well established and highly effective in resistant
depression.78,79 Electrical stimulation is applied bilaterally or unilaterally to the head to
induce a seizure. ECT requires anesthesia and can cause transient cognitive side effects
or amnesia and is therefore generally used after patients have failed pharmacologic trials
and/or in very severe forms of depression.80 Hypertension and arrhythmias have also
been noted, but these complications occur more frequently in patients with preexisting
cardiac complications and can be well managed in clinical contexts.81 Hence, there are
no absolute contraindications, although relative contraindications include coronary
artery disease, arrhythmia, and increased intracranial pressure or lesions.
Other FDA-approved treatments for resistant depression include transcranial
magnetic stimulation (TMS) and vagus nerve stimulation (VNS). TMS (a noninvasive
brain depolarization induced by a magnetic field) has shown modest efficacy (14%
remission rates) but few adverse effects in subjects with MDD with mild to moderate
levels of treatment resistance.82 A recent meta-analysis of more than 34 randomized,
sham-controlled trials, including more than 1000 patients, supports the efficacy of
TMS as both monotherapy and as an adjunctive treatment to pharmacotherapy.83
VNS requires a surgically implanted device sending electrical impulses to ascending
fibers of the vagus nerve, and has shown no significant efficacy compared with
188 Soleimani et al

placebo after 3 months, but increasing efficacy in open treatment up to 1 year in pop-
ulations with severe treatment-resistant depression.84 Phototherapy, which involves
the application of bright light, may be particularly useful in seasonal depression.85
Lifestyle changes and alternative remedies with some efficacy in the treatment of
depression include physical exercise, and some dietary supplements (eg, u-3 fatty
acids, S-adenosyl methionine, St John’s wort).86

PHASES OF TREATMENT

The recently published APA Practice guidelines for the treatment of patients with major
depressive disorder, 3rd edition87 incorporates insights from large studies in MDD in
the last decade, including the large National Institute of Mental Health–sponsored
Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. According
to the APA guidelines, management of the patient with MDD can be framed in the
context of 3 phases.
The acute phase of treatment is focused on the acutely depressed patient and
begins with tailoring a strategy that is based on the severity of the symptoms, history
of prior positive responses, presence of other psychiatric symptoms, side effect profile
of the medication, and the patient’s preference (eg, pharmacotherapy without/with
psychotherapy for the mild/moderate symptoms, ECT for severe depression, and
presence of psychotic features or catatonia). In cases of treatment failure (ie, no
improvement after 4–8 weeks of treatment), raising antidepressant doses to the
optimal tolerable level (optimization) should be considered before switching to another
drug within the same class or in another class of drugs. For partial responders, combi-
nation of antidepressant medications (adding buproprion, low-dose TCA, mirtazapine,
or buspirone) or augmentation strategies (with atypical antipsychotics, lithium, triiodo-
thyronine, psychostimulants, or dopaminergic agents) can be used before switching
medications.

Box 6
Helpful clinical recommendations

 Explain depression as an illness associated with neurochemical dysregulation in the brain,

rather than a personal weakness or fault
 More than 60% of patients with MDD are at risk for recurrence; patients with recurrent
depression should be educated about the early signs of depression; some may require
lifelong antidepressant therapy
 Education about the anticipated side effects of the medications will improve patient
compliance
When to refer to, or consult with, a psychiatrist:
 Significant risk for suicide or homicide (acute suicidal risk may require a psychiatric
hospitalization)
 Current or plans for future pregnancy
 Poor social support
 Disability caused by depression
 Suboptimal response to 1 or 2 adequate treatments
 Comorbid psychiatric problems (psychosis, mania, severe anxiety, substance abuse, panic
attacks, posttraumatic stress disorder, dementia)
 Need for alcohol or illicit drug detoxification
 Major Depression: Diagnosis and Treatment 189

The continuation treatment refers to the phase after the initial remission of symp-
toms. The antidepressant treatment that led to remission in the acute phase should
be continued for an additional 6 to 9 months with full antidepressant doses to
decrease the risk of relapse.
The maintenance treatment is the phase during which patients with high risk of
relapse (ie, patients with a history of 3 or more major depressive episodes) might
benefit from indefinite maintenance therapy to prevent the risk of recurrence.

SUMMARY

MDD is a common illness associated with significant morbidity and mortality. The
prevalence of MDD is even higher in medically ill patients. It is important for clinicians
to suspect the diagnosis of MDD in patients with suggestive symptoms or risk factors.
Such suspicion should be followed by a review of diagnostic symptoms (possibly
through the administration of standardized scales) with an emphasis on the presence
of suicidal thinking, and by laboratory tests to differentiate from medical causes of
depression. Although several pharmacotherapies, psychotherapies, and somatic
treatments have been shown to effectively treat MDD, a large number of patients
do not improve sufficiently with any single treatment and can benefit from switching
or combining different antidepressant modalities. Patients with severe depression
and/or suicidal ideation, and those having failed several antidepressant treatments,
would benefit from consultation with, or referral to, a psychiatrist (Box 6).

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